title: The structure of MESD45-184 brings light into the mechanism of LDLR family folding.
abstract: Mesoderm development (MESD) is a 224 amino acid mouse protein that acts as a molecular chaperone for the low-density lipoprotein receptor (LDLR) family. Here, we provide evidence that the region 45-184 of MESD is essential and sufficient for this function and suggest a model for its mode of action. NMR studies reveal a β-α-β-β-α-β core domain with an α-helical N-terminal extension that interacts with the β sheet in a dynamic manner. As a result, the structural ensemble contains open (active) and closed (inactive) forms, allowing for regulation of chaperone activity through substrate binding. The mutant W61R, which is lethal in Drosophila, adopts only the open state. The receptor motif recognized by MESD was identified by in vitro-binding studies. Furthermore, in vivo functional evidence for the relevance of the identified contact sites in MESD is provided.
authors.affiliation: Department of NMR-Supported Structural Biology, Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Köhler
authors.forename: Janet K
authors.initials: JK
authors.lastname: Lighthouse
authors.forename: Tobias
authors.initials: T
authors.lastname: Werther
authors.forename: Olav M
authors.initials: OM
authors.lastname: Andersen
authors.forename: Annette
authors.initials: A
authors.lastname: Diehl
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.forename: Jianguang
authors.initials: J
authors.lastname: Du
authors.forename: Bernadette C
authors.initials: BC
authors.lastname: Holdener
authors.forename: Hartmut
authors.initials: H
authors.lastname: Oschkinat
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004331:Drosophila melanogaster; D015870:Gene Expression; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; C472170:MESD protein, mouse; D018832:Molecular Chaperones; D020033:Protein Isoforms; D011994:Recombinant Proteins